R. R. Dandu et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2151–2153
2153
O
O
O
HO
O
O
a
HO
O
N
+
O
N
OH
O
5
4
3
HO
HO
b
c
d
O
N
O
NH
7
6
O
O
e
O
S
O
N
O
N
N
N
O
10
8
O
O
Scheme 1. Reagents and conditions: (a) pyrrolidine, MeOH, reflux, 23 h, 82%; (b) (i) NaBH4, EtOH, rt, 2 h, 90%, (ii) TFA, Et3SiH, 5 °C to rt, 14 h, 72%; (c) cyclobutanone,
NaCNBH3, DMF–MeOH, rt, 5 h, 50%; (d) tert-butyl 4-hydroxypiperidine-1-carboxylate, Ph3P, DEAD, THF, rt, 72%; (e) (i) TFA, CH2Cl2, rt, 2 h, 85% ? 9, (ii) H3CSO2Cl, DIEA, CH2Cl2,
0 °C to rt, 2 h, 80%.
Ann. Rep. Med. Chem. 2007, 42, 49; (h) Raddatz, R.; Tao, M.; Hudkins, R. L. Curr.
Top. Med. Chem. 2010, 10, 153; (i) Brioni, J. D.; Esbenshade, T. A.; Garrison, T. R.;
Bitner, S. R.; Cowart, M. D. J. Pharmacol. Exp. Ther. 2011, 336, 38; (j) Lovenberg, T.
W.; Roland, B. L.; Wilson, S. J.; Jiang, X.; Pyati, J.; Huvar, A.; Jackson, M. R.;
Erlander, M. G. Mol. Pharmacol. 1999, 55, 1101.
(t = 1.8 h, Vd = 1.6 L/kg, CL = 10 mL/min/kg) but exhibited poor
oral PK in rat. The amide H3R targets (14–16) exhibited excellent
½
liver microsomal stability (t >40 min) and also had very good
½
selectivity against cytochrome P450 enzymes (IC50 >30 lM) dem-
2. (a) Bacon, E. R.; Bailey, T. R.; Becknell, N. C.; Chatterjee, S.; Dunn, D.; Hostetler, G.
A.; Hudkins, R. L.; Josef, K. A.; Knutsen, L.; Tao, M.; Zulli, A. L. US2010273779,
2010.; (b) Hudkins, R. L.; Raddatz, R.; Tao, M.; Mathiasen, J. R.; Aimone, L. D.;
Becknell, N. C.; Prouty, C. P.; Knutsen, L.; Yazdanian, M.; Moachon, G.; Ator, M.
A.; Mallamo, J. P.; Marino, M. J.; Bacon, E. R.; Williams, M. J. Med. Chem. 2011, 54,
4781; (h) Raddatz, R.; Hudkins, R. L.; Mathiasen, J. R.; Gruner, J. A.; Flood, D. G.;
Aimone, L. D.; Le, S.; Schaffhauser, H.; Gasior, M.; Bozyczko-Coyne, D.; Marino,
M. J.; Ator, M. A.; Bacon, E. R.; Mallamo, J. P.; Williams, M. J. Pharmacol. Exp. Ther.
2012, 340, 124.
3. (a) Hudkins, R. L.; Aimone, L. D.; Bailey, T. R.; Bendesky, R. J.; Dandu, R.; Dunn, D.
D.; Gruner, J. A.; Josef, K. A.; Lin, Y.; Lyons, J.; Marcy, V. R.; Mathiasen, J. R.;
Sundar, B. G.; Tao, M.; Zulli, A. L.; Raddatz, R.; Bacon, E. R. Bioorg. Med. Chem. Lett.
2011, 21, 5493; (b) Sundar, B. G.; Bailey, T.; Bacon, E.; Aimone, L.; Huang, Z.;
Lyons, J.; Raddatz, R.; Hudkins, R. L. Bioorg. Med. Chem. Lett. 2011, 21, 5543; (c)
Tao, M.; Raddatz, R.; Aimone, L. D.; Hudkins, R. L. Bioorg. Med. Chem. Lett. 2011,
21, 6126; (d) Dandu, R.; Gruner, J. A.; Mathiasen, J. R.; Aimone, L. D.; Hostetler, G.
A.; Benfield, C.; Bendesky, R. J.; Marcy, V. R.; Raddatz, R.; Hudkins, R. L. Bioorg.
Med. Chem. Lett. 2011, 21, 6362; Becknell, N. C.; Lyons, J. A.; Aimone, L. D.;
Gruner, J. A.; Mathiasen, J. R.; Rita Raddatz, R.; Hudkins, R. L. Bioorg. Med. Chem.
Lett. 2011, 21, 7076; (f) Hudkins, R. L.; Aimone, L. D.; Dandu, R.; Dunn, D.;
Gruner, J. A.; Huang, Z.; Josef, K. A.; Lyons, J.; Mathiasen, J. R.; Tao, M.; Zulli, A. L.;
Raddatz, R. Bioorg. Med. Chem. Lett. 2012, 22, 194; (g) Becknell, N. C.; Dandu, R.;
Lyons, J. A.; Aimone, L. D.; Raddatz, R.; Hudkins, R. L. Bioorg. Med. Chem. Lett.
2012, 22, 186.
onstrated acceptable iv PK properties but displayed poor oral expo-
sure in rat, (Table 2). Furthermore, compounds 10, 13, 15, and 16
exhibited good aqueous solubility (PH7.4 >0.1 to 0.2 mg/mL).
In summary,
a
new series of 10-cyclobutyl-6-(4-piperidyl-
oxy)spiro[benzopyran-2,40-piperidine] derivatives was identified
as high affinity H3R ligands. Simple alkyl sulfonamide and alkyl
amide analogs of 10-cyclobutyl-6-(4-piperidyloxy)spiro[benzopy-
ran-2,40-piperidine] exhibited high H3R target affinity, receptor
subtype (hH1, hH2, and hH4) selectivity, metabolic stability, CYP
isoforms selectivity, aqueous solubility, and favorable iv pharma-
cokinetic properties but demonstrated poor oral exposure in rat.
Further optimization of spirobenzopyran piperidine ether series
to improve the oral bioavailability and lead to a nomination candi-
date will be reported in due course.
Supplementary data
Supplementary data associated with this article can be found, in
4. (a) Yang, L.; Morriello, G.; Prendergast, K.; Cheng, K.; Jacks, T.; Chan, W. W.;
Schleim, K. D.; Smith, R. G.; Patchett, A. A. Bioorg. Med. Chem. Lett. 1998, 8, 107;
(b) Jean-philippe, L.; Chun Sing, L.; Oscar Miguel, M. WO2010094120, 2010.
5. These studies will be published elsewhere.
References and notes
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J. A.; Bonaventure, P.; Dugovic, C.; Shelton, J.; Lord, B.; Miller, K.; Dvorak, L. K.;
Lovenberg, T. W.; Carruthers, N. J. Euro. J. Med. Chem. 2009, 44, 4098.
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